Prediction of metabolic clearance from human hepatocyte CLint Results are expressed as the mean CLint ± standard deviation from n >3 donors. Results not expressing a S.D. are from <3 donors. The CLint determinations were carried out as described under Materials and Methods. All substrates were not incubated in the same donor livers. Assays were performed in triplicate. Compounds are classified as neutrals (N), bases (B), or zwitterions (Z).
Compound | N/B/Z | Donors | Human Hepatic CLint | Scaled CLint | Scaled CLmet | Observed CLmeta | Observed in Vivo CLint | Enzymes Responsible for Metabolism |
|---|---|---|---|---|---|---|---|---|
| μl/min/106 cells | ml/min/kg | |||||||
| Bromocriptine | N | 1 | 37 | 98 | 17 | 15 | 60 | CYP3A4 |
| Caffeine | N | 1 | 3.3 | 8.7 | 6.1 | 2.1 | 2.3 | CYP1A2 |
| Carbamazepine | N | 1 | 2.0 | 5.3 | 4.2 | 0.4 | 0.4 | CYP3A4 > 2C8/9 |
| Cimetidine | N | 9 | 1.2 ± 0.4 | 3.2 | 2.7 | 3.2 | 3.8 | P450 |
| Cyclosporin A | N | 8 | 3.5 ± 1.5 | 9.2 | 6.3 | 4.7 | 6.1 | CYP3A4 |
| Diazepam | N | 1 | 0.3 | 0.8 | 0.8 | 0.4 | 0.4 | CYP2C19 > 3A |
| Ethinylestradiol | N | 5 | 7.0 ± 2.0 | 19 | 9.6 | 5.4 | 7.4 | UGT1A1>CYP3A4 |
| Famotidine | N | 6 | <1.0 | <2.3 | 2.1 | 2.3 | P450 (minor) | |
| Isradipine | N | 1 | 18 | 47 | 14 | 8 | 13 | CYP3A4 |
| Lorazepam | N | 1 | 1.0 | 2.6 | 2.3 | 1 | 1.1 | UGT |
| Midazolam | N | 5 | 14 ± 8.0 | 37 | 13 | 6.6 | 9.9 | CYP3A4 |
| Nifedipine | N | 5 | 5.6 ± 1.5 | 15 | 8.5 | 8.5 | 15 | CYP3A4 |
| Nitrendipine | N | 7 | 7.4 ± 3.5 | 20 | 9.9 | 20 | CYP3A4 | |
| Omeprazole | N | 2 | 1.7 | 4.5 | 3.7 | 7.5 | 12 | CYP2C19 > 3A4 |
| Prazosin | N | 7 | 2.3 ± 1.7 | 6.1 | 4.7 | 2.7 | 3.1 | P450 |
| Propofol | N | 5 | 107 ± 26 | 283 | 19 | 11 | 24 | UGT1A9 >> P450 |
| Ritonavir | N | 7 | 2.1 ± 3.0 | 5.5 | 4.3 | 1.2 | 1.3 | CYP3A4 >> 2D6 |
| Temazepam | N | 2 | 2.0 | 5.3 | 4.2 | 1.3 | 1.4 | UGT > P450 |
| Triazolam | N | 2 | 1.0 | 2.6 | 2.3 | 2.5 | 2.9 | CYP3A4 |
| Zileuton | N | 16 | 2.1 ± 1.8 | 5.5 | 4.3 | 6.0 | 8.6 | UGT |
| Acebutolol | B | 4 | 1.8 ± 1.5 | 4.8 | 3.8 | 4.1 | 5.2 | Acetylation |
| Atenolol | B | 5 | <1.0 | <2.3 | <1.0 | Insignificant | ||
| Bepridil | B | 1 | 2.0 | 5.3 | 4.2 | 5.3 | 7.2 | CYP3A4 |
| Betaxolol | B | 6 | 2.5 ± 1.0 | 6.6 | 4.9 | 3.9 | 4.8 | P450 |
| Bisoprolol | B | 8 | 1.6 ± 1.4 | 4.2 | 3.5 | 1.3 | 1.4 | P450 |
| Carvedilol | B | 5 | 35 ± 11 | 93 | 16 | 8.7 | 15 | P450/UGT |
| Chlorpheniramine | B | 4 | 2.8 ± 1.3 | 7.4 | 5.4 | 1.3 | 1.4 | P450 >> UGT |
| Clozapine | B | 1 | 6.0 | 16 | 8.8 | 7.4 | 12 | CYP1A2 >> UGT, CYP2D6, 3A4 |
| Codeine | B | 2 | 23 | 61 | 15 | 7.5 | 12 | UGT > CYP2D6 > CYP3A4 |
| Desipramine | B | 1 | 3.0 | 7.9 | 5.7 | 12 | 30 | CYP2D6 > UGT |
| Dextromethorphan | B | 81 | 7.6 ± 8.1 | 20 | 10.0 | 6.0 | 8.6 | CYP2D6 > 3A/2C19 |
| Diltiazem | B | 88 | 9.0 ± 5.0 | 24 | 11 | 12 | 30 | CYP3A4 |
| Diphenhydramine | B | 1 | 6.0 | 16 | 8.8 | 9.6 | 19 | P450 >> UGT |
| Doxepin | B | 1 | 13 | 34 | 13 | 14 | 47 | P450 |
| Fluoxetine | B | 1 | 1.0 | 2.6 | 2.3 | 7.8 | 13 | CYP2D6 |
| Granisetron | B | 4 | 9.0 ± 8.7 | 24 | 11 | 11 | 24 | CYP3A4 |
| Imipramine | B | 3 | 8.0 ± 2.5 | 21 | 10 | 17 | 113 | CYP2D6/1A2/2C19/3A/ UGT1A4 |
| Metoprolol | B | 5 | 7.0 ± 2.9 | 19 | 9.6 | 13 | 37 | CYP2D6 |
| Morphine | B | 2 | 24 | 63 | 15 | 18 | 180 | UGT2B7 |
| Nadolol | B | 3 | <1.0 | <2.3 | 0.8 | 0.8 | Insignificant | |
| Naloxone | B | 2 | 216 | 570 | 19 | 13 | 37 | UGT2B7 |
| Ondansetron | B | 5 | 1.4 ± 0.5 | 3.7 | 3.1 | 5.9 | 8.4 | CYP2D6, 1A2, 3A4 |
| Pindolol | B | 4 | 2.8 ± 1.0 | 7.4 | 5.4 | 4.2 | 5.3 | P450 > UGT |
| Pirenzepine | B | 4 | <1.0 | <2.3 | <1.0 | Insignificant | ||
| Propranolol | B | 90 | 10 ± 5.0 | 26 | 11 | 16 | 80 | CYP2D6 > 1A2/2C19/UGT |
| Ranitidine | B | 5 | 1.0 ± 0.0 | 2.6 | 2.3 | 2.9 | 3.4 | FMO3 / P450 |
| Scopolamine | B | 1 | 7.0 | 19 | 9.6 | 11 | 24 | Esterase |
| Triprolidine | B | 4 | 4.3 ± 3.3 | 11 | 7.2 | 8 | 13 | P450 |
| Verapamil | B | 86 | 18 ± 12 | 46 | 14 | 15 | 60 | CYP3A4 |
| Cetirizine | Z | 5 | <1.0 |
| <2.3 | <1.0 |
| P450 (minor) |